Zinc regulates iNOS-derived nitric oxide formation in endothelial cells.
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Cortese-Krott MM, Kulakov L, Oplander C, Kolb-Bachofen V, Kroncke KD, Suschek CV
Zinc regulates iNOS-derived nitric oxide formation in endothelial cells.
Redox Biol. 2014 Jul 16;2:945-54. doi: 10.1016/j.redox.2014.06.011. eCollection 2014.
- PubMed ID
- 25180171 [ View in PubMed]
- Abstract
Aberrant production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathogenesis of endothelial dysfunction and vascular disease. Mechanisms responsible for the fine-tuning of iNOS activity in inflammation are still not fully understood. Zinc is an important structural element of NOS enzymes and is known to inhibit its catalytical activity. In this study we aimed to investigate the effects of zinc on iNOS activity and expression in endothelial cells. We found that zinc down-regulated the expression of iNOS (mRNA+protein) and decreased cytokine-mediated activation of the iNOS promoter. Zinc-mediated regulation of iNOS expression was due to inhibition of NF-kappaB transactivation activity, as determined by a decrease in both NF-kappaB-driven luciferase reporter activity and expression of NF-kappaB target genes, including cyclooxygenase 2 and IL-1beta. However, zinc did not affect NF-kappaB translocation into the nucleus, as assessed by Western blot analysis of nuclear and cytoplasmic fractions. Taken together our results demonstrate that zinc limits iNOS-derived high output NO production in endothelial cells by inhibiting NF-kappaB-dependent iNOS expression, pointing to a role of zinc as a regulator of iNOS activity in inflammation.